Stable aqueous suspension

ABSTRACT

An aqueous suspension of a hydrophobic nutrient is disclosed. In particular, the nutrient, in ester form, is combined with a selected dispersion aid and a dispersion agent(s), and then dispersed in an aqueous medium to form the suspension.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to a stable aqueous suspension comprisinga nutrient, as well as to a method of rendering a normally hydrophobicnutritional compound or ingredient dispersible in water or in an aqueoussystem.

[0003] 2. Description of the Related Art

[0004] Nutritional compounds, i.e. nutritional supplements, have beenshown to help prevent the onset of undesirable conditions in man. Thesesubstances have been identified as either essential to human health(e.g. vitamins), or may, based on the increasing compilation of studies,play a role in maintaining health. For example, phytosterol and/orphytostanol esters have been shown to reduce serum cholesterol levels inman (mammals) upon consumption, and subsequent digestion in the gut. Themechanism for this is not completely known. Scientists theorize thatthese compounds block absorption of cholesterol produced and releasedfrom the body through the normal hepatic function, or consumed as acomponent of food. In reducing serum cholesterol levels, current wisdomdeduces that heart and circulatory health may be maintained bypreventing such conditions as arteriosclerosis, myocardial infarction,etc.

[0005] Nutritional ingredients, such as lutein, are currently availablein tablets or other dry forms because heretofore they could not besatisfactorily dispersed in water. The nutritional ingredients, such asthe phytosterols, phytostanols, lutein, isoflavones, Coenzyme Q₁₀, aretypically hydrophobic and are not ordinarily dispersible in aqueoussystems because they are only slightly water or oil soluble, if to anydegree at all.

[0006] The nutritional ingredients are desirable for use in beveragesand cosmetics, in the form of aqueous suspensions, dispersions, orliposomes. Accordingly, a means for rendering these ingredients waterdispersible or dispersible in an aqueous system is needed and desired.

SUMMARY OF THE INVENTION

[0007] This invention relates to a stable suspension comprising anutrient or nutritional ingredient. In particular, the nutrient is in anester form and is associated with a dispersion aid and a dispersionagent.

DETAILED DESCRIPTION OF THE INVENTION

[0008] This invention involves a stable aqueous suspension whichcomprises a nutrient or a nutritional compound or ingredient.

[0009] A suitable nutrient or nutritional ingredient is one which issuitable for therapeutic treatment of an animal, e.g. a human being, byingestion, e.g. via a beverage, or by topical application, e.g. via alotion or cream, but which is unfortunately typically insoluble or onlyslightly soluble in water at room temperature, e.g. 20° C. to 25° C.,i.e. it is typically hydrophobic. It is these ingredients which are thesubject of this invention. Some suitable nutrients or nutritionalingredients include (1) a compound of the formula,

[0010] where R is OH, β-glucoside, 6″-O-acetylglucoside, or6″-O-malonylglucoside; R′ is H or OH; and R″ is H or OCH₃; such asisoflavone, e.g. a soybean derived isoflavone, and a substitutedisoflavone, such as daidzein, genistein and glycitein; (2) lutein, (3) aCoenzyme Q_(n), where n is an integer of 1-12, e.g. Coenzyme Q₁₀, (4) aphytosterol, e.g. a stigmasterol, sitosterol, fucosterol,brassicasterol, campesterol, clionasterol, desmosterol, chalinosterol,poriferasterol, (5) a phytostanol, e.g. α or β sitostanol, campestanol,brassicastanol, clionastanol, stigmastanol, desmostanol, chalinostanol,poriferastanol, 22, 23 dihydrobrassicastanol, etc. and (6) a mixture ofany of the foregoing ingredients.

[0011] For purposes of the dispersions of this invention, which areintended for therapeutic use or as additives in association with atherapeutic treatment of animals, e.g. a human, a particular nutrient ormixture of nutritional ingredients is present in the inventive aqueousdispersions or suspensions in an effective nutritional amount, that isan amount which causes its desired nutritional or therapeutic effect.

[0012] The term “amount” as used herein refers to quantity orconcentration as appropriate to the context. The amount of nutrient thatconstitutes a nutritional amount varies according to factors such aspotency of the particular ingredient or mixture of ingredients, the modeof administration and the mechanical system used to administer thedispersion. A normally effective amount of a particular nutrient can beselected by those of ordinary skill in the art with due consideration ofsuch factors. Generally, a nutritionally effective amount will be from0.005 parts by weight to about 25 parts by weight based on 100 parts byweight of the dispersion or suspension.

[0013] A suitable aqueous system or medium is selected. A suitableaqueous system or medium for the dispersions or suspensions of thisinvention include water and an aqueous solution of an organic alcohol of1 to 6 carbon atoms, e.g. ethanol, propylene glycol, glycerin, etc., anda mixture of the foregoing; present in an amount of up to 10 percent(10%) by weight. The aqueous system is one which will permit a stabledispersion or suspension to be formed therein when combined with theselected nutrient or mixture of nutrients, which in turn is destined tobe in the form of at least a mono-ester associated with a suitabledispersion aid. The aqueous system is present in an amount which affordsthe desired dispersion and is dependent upon the selected nutrient ormixture of nutritional ingredients with the selected dispersion aid.Typically, the aqueous system comprises 55 to 95 weight percent of thedispersion or suspension.

[0014] The selected nutrient must first be converted to an ester, e.g. amono-, di-, tri-ester, etc., if it does not already exist as at least amono-ester. Such conversion, if required, is conventionally carried out.In this regard, reference is made to such standard text as Briehler, andPearson, “Survey of Organic Synthesis”, Volumes 1 and 2, John Wiley &Sons.

[0015] Additionally, reference is made to Ingmar Westar et al., WO09956558; M. P. van Amerongen et al., EP 00911385 A1 which describes thepreparation of stanol, phytosterol and phytostanol esters.

[0016] A suitable dispersion aid is selected, i.e. an agent which whencombined or associated with the nutrient ester modifies such ester fromits crystalline form or morphous form to a dissolved form. The thenmodified nutrient compound, i.e. ester, can then be further formulatedor treated, e.g. pulverized, particularized, homogenized, liquefied,dispersed in oil carrier, whereby it can be easily dispersed in water oran aqueous medium as a suspension.

[0017] A suitable dispersion aid includes (1) a triglyceride, such assunflower oil, soy bean oil, olive oil; a medium chain triglyceride i.e.triglycerides with mixed fatty acids of C₆ to C₁₂ lengths, such assn-glyceryl-1-caprylate, -2-caprate, -3-caprylate, etc., and a mixtureof any of the foregoing, (2) an essential oil extractive, such as orangeoil, lime oil, clove oil, oregano oil, peppermint oil, cinnamon oil,etc., and a mixture of the foregoing; (3) night primrose oil; (4) fishoils; (5) and a mixture of any of the foregoing aids.

[0018] The nutrient in ester form is combined or mixed with thedispersion aid, typically at a temperature ranging from 20 to 80° C.,e.g. 70-75° C., for 2 to 10 minutes to form the nutrient esterassociated with the dispersion aid. By “associate” or “associated” meansthat the nutrient ester has either reacted with the dispersion aid orhas physically interacted with the dispersion aid whereby it is eithermixed therewith, encapsulated, wholly or partially, thereby, or becomespart of the interstices thereof, solubilized or diluted.

[0019] A suitable dispersion agent is selected from (1) a lecithin,derived from soybean or derived from egg which contain a complex mixtureof phospholipids consisting mainly of phosphatidylcholine,phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acidcombined with varying amounts of other substances such as triglycerides:the lecithin can be of standard grade or can be modified or refinedlecithin e.g. deoiled, hydrogenated, hydroxylated, enzyme modified,acetylated, etc.; (2) a hydrocolloid, e.g. xanthan gum, starch, pectin,gelatin, guar gum, carrageenan, methylcellulose, hydroxypropylcellulose; (3) a surfactant, e.g. cetylpyridinium chloride, polysorbate80, sorbitan monostearate, polyglycerol esters, block copolymers ofpropylene oxide, ethylene oxide; (4) a mixture of any of the forgoingdispersion agents.

[0020] An aqueous dispersion of the selected nutrient/aid combinationutilizes the dispersion agent in an amount effective to form andstabilize the resultant aqueous dispersion relative to an identicalaqueous formulation not containing the dispersion agent, such that theactive ingredient does not settle, cream or flocculate after agitationso quickly as to prevent reproducibility, e.g. reproducible dosing.Reproducible application, e.g. dosing, can be achieved if the resultantaqueous suspension is substantially uniform for minimally 1 to 2 hoursafter agitation thereof. The particular amount of dispersion agent thatconstitutes an effective amount is dependent upon the particulardispersion agent, the particular aqueous system or medium employed andthe particular nutritional ingredient/aid combination, or mixture ofingredients employed. It is therefore not practical to enumerate aspecific effective amount for use with specific dispersions orformulations of the invention, but such amount can readily be determinedby those of ordinary skill in the art with due consideration of thefactors set forth above. Generally, however, the dispersion agent can bepresent in a formulation in an amount from about 0.01 percent by weightto about 20 percent by weight, more preferably about 0.05 percent toabout 10 percent by weight, most preferably 0.5 percent to 5 percent byweight, based on the total weight of the dispersion or formulation.

[0021] Typically, the dispersion aid, e.g. sunflower oil, is combinedwith the active ingredient or nutritional agent, e.g. phytosterolesters, at a temperature of 20° to 80° C. and is mixed for 2 to 10minutes. Thereafter the combination is added to water containingdispersion agents, and is agitated thereto to form a mixture. Theresultant mixture is then subjected to a high shear treatment using anycommercially available equipment, e.g. Microfluidics M110, at a shearpressure of 6500 to 24,000 psi, and preferably at a shear pressure of7000 to 20,000 psi, and most preferably at a shear 10,000 to 12,000 psi,whereby a particle size of the active ingredient typically is less than500 nm, preferably less than 300 nm, most preferably less than 250 nm,to form the desired aqueous dispersion or suspension.

[0022] It is noted that the procedure described above can be modified,namely the order of addition of the nutrient/aid combination, dispersionagent, and aqueous system to form the initial aqueous mixture, i.e.preceding to the described high shear treatment of the mixture.

[0023] The resultant aqueous nutrient dispersion can then be furtherformulated and administered to a patient, e.g. a mammal such as a humanbeing, by any conventional means, such as topically, orally; etc.Typically the dispersion or suspension is combined with other drugs,adjuvants, etc. in the form of a cream or lotion, e.g. a cosmetic, or inthe form of a liquid, e.g. a beverage.

EXAMPLES Example 1

[0024] SELIN® brand phytosterol fatty acid esters from Cognis (6.0 g)was dissolved in 24.0 g of NUSUN® oil, from Archer Daniels Midland, ahigh oleic acid sunflower oil, at 36° C. The resultant solution wasadded to an aqueous system comprising 78.5 percent by weight ofdeionized water (157 g), 4.0 percent by weight BLENDMAX K® lecithin fromCentral Soya (8 g) and 2.5 percent polysorbate 80 (5 g). The resultantmixture was treated two times with a Microfluidizer® M110T fromMicrofluidics at 8,000 psi shear pressure to obtain a stable dispersion.

Example 2

[0025] The procedure of Example 1 was repeated using 15 g of SELIN®, 15g of NUSUN® oil, 157 g of deionized water, 8 g of BLENDMAX K®, and 5 gof polysorbate 80 to obtain a stable dispersion.

Example 3

[0026] SELIN® (6 g) was combined with NUSUN® oil (24 g) and heated at60° C. for 15 minutes to form a solution. Deionized water (1155.8 g) andpolysorbate 80 (5 g) were mixed together and heated at 60° C. for 15minutes and then combined with the solution. BLENDMAX K® lecithin (8 g),citric acid (0.6 g) and potassium sorbate (0.6 g) were added to thecombined solution with mixing and then the resultant mixture was passedthrough a M110T Microfluidizer®, two times at a shear pressure of 8,000psi. A mean particle size of the stable dispersion of 178.3 nm wasobtained.

Example 4

[0027] The procedure of Example 3 was repeated with 10 g of SELIN®, 20 gof NUSUN® oil, 155.8 g of deionized water, 8 g of BLENDMAX K®, 5 g ofpolysorbate 80, 0.6 g of citric acid and 0.6 g of potassium sorbate. Amean particle size of 194.6 nm of the stable dispersion was obtained.

Example 5

[0028] An experiment was conducted to see how high a percentage of thephytosterol esters could be incorporated into a stable dispersion. Thegeneral procedure was to combine BLENDMAX K®, Polysorbate 80, NUSUN® oiland SELIN® and mix these components thoroughly at a temperature of60°-65° C. To this mix was added deionized water, and the resultantmixture was mixed with a Silverson® high shear mixer. While mixing,citric acid and potassium sorbate were added. Once the mixture becameuniform, it was passed twice through a M110T Microfluidizer® at a shearpressure of 8,000 psi. The highest percentage of the SELIN in a stabledispersion obtained was 10.0 percent by weight, using the followingweight percentages of the ingredients. Deionized Water 72.9 BLENDMAX ®4.0 Polysorbate 80 2.5 NUSUN ® Oil 10.0 SELIN ® 10.0 Citric acid 0.3Potassium sorbate 0.3

Example 6

[0029] The procedure of Example 5 was repeated for lutein esters A(g)B(g) Deionized Water 72.9 67.9 BLENDMAX ® 4.0 4.0 Polysorbate 80 2.5 2.5NUSUN ® Oil 19.8 24.75 Citric acid 0.3 0.3 Potassium sorbate 0.3 0.3Xangold ® Lutein esters 0.2 0.25

[0030] Stable dispersions were obtained.

Example 7

[0031] 7.5 g of Xangold®, a 15% lutein ester suspension in vegetable oilfrom Cognis, was dissolved with 17.5 g of orange oil at 65° C. 4.0 g ofBLENDMAX K®, 2.5 g of Polysorbate 80 were added and heated at 65° C. forseveral minutes. To the heated mixture was added 67.9 g of Deionizedwater, 0.3 g citric acid, and 0.3 g potassium sorbate while mixing witha Silverson® high shear mixer. The resultant mixture was then passedtwice through a M110 Microfluidizer® at a shear pressure of 10,000 psito yield a stable dispersion.

Example 8

[0032] The procedure of Example 7 was repeated using 3.75 g of Xangold®lutein esters and 21.25 g of olive oil instead of orange oil to obtain astable dispersion.

We claim:
 1. An aqueous suspension of a hydrophobic nutrient whichcomprises, the nutrient in ester form associated with a dispersion aidselected from the group consisting of a triglyceride, an essential oilextractive, night primrose oil, fish oil, and a mixture of any of theforegoing dispersion aids; a dispersion agent: and an aqueous mediuminto which said associated nutrient is suspended.
 2. The suspension asdefined in claim 1, wherein said associated nutrient is in a fullydispersed, uniform form in the aqueous medium.
 3. The suspension asdefined in claim 2, wherein the particles size of said fully dispersed,uniform form ranges from 50 to 400 nm.
 4. The suspension as defined inclaim 1, wherein said ester is an ester of a nutritional compoundselected from the group consisting of (a) a phytosterol selected fromthe group consisting of stigmasterol, sitosterol, fucosterol,brassicasterol, campesterol, clionasterol, desmosterol, chalinosterol,poriferasterol, and any mixture of the foregoing phytosterols; (b) aphytostanol, selected from the group consisting of e.g. α sitostanol orβ sitostanol, campestanol, brassicastanol, clionastanol, stigmastanol,desmostanol, chalinostanol, poriferastanol, 22, 23 dihydrobrassicastanoland any mixture of the foregoing phytostanols; (c) lutein, (d) CoenzymeQ₁₀, (e) isoflavones, (f) and a mixture of any of the foregoing esters.5. The suspension as defined in claim 1, wherein said triglyceride isselected from the group consisting of sunflower oil, soy bean oil, oliveoil, a medium chain triglyceride, selected from the group containingfatty acids ranging from C₆ to C₁₂, and a mixture of any of theforegoing triglycerides.
 6. The suspension as defined in claim 1,wherein said essential oil extractive is one selected from the groupconsisting of orange oil, lime oil, clove oil, oregano oil, peppermintoil, cinnamon oil, and a mixture of any of the foregoing extractives. 7.The suspension as defined in claim 1, wherein said dispersion agent isselected from the group consisting of (a) a lecithin, (b) ahydrocolloid, (c) a surfactant and (d) a mixture of any of the foregoingdispersion agents.
 8. The suspension as defined in claim 7, wherein saidlecithin is selected from the group consisting of lecithin derived fromsoybean and lecithin derived from egg.
 9. The suspension as defined inclaim 7, wherein said hydrocolloid is selected from a group consistingof xanthan gum, starch, pectin, gelatin, guar gum, carrageenan,methylcellulose, hydroxypropyl cellulose and a mixture of the foregoinghydrocolloids.
 10. The suspension as defined in claim 7, wherein saidsurfactant is selected from the group consisting of cetylpyridiniumchloride, polysorbate 80, sorbitan monostearate, a polyglycerol ester, ablock copolymer of propylene oxide, ethylene oxide and a mixture of anyof the foregoing surfactants.
 11. A method of rendering a hydrophobicnutritional compound water dispersible, which comprises: (a) treating anester form of the compound with a dispersion aid selected from the groupconsisting of a triglyceride, an essential oil extractive, nightprimrose oil, fish oil, and a mixture of any of the foregoing dispersionaids, to form a modified nutrient compound; (b) combining a dispersionagent with said modified nutrient compound in an aqueous medium to forman aqueous suspension; and treating said aqueous to a high shear forceto form a stable aqueous suspension.
 12. The method as defined in claim11, wherein said stable suspension has a mean particle size ranging from50 to 400 nm.
 13. The method as defined in claim 11, wherein said esteris an ester of a nutritional compound selected from the group consistingof (a) a phytosterol, selected from the group consisting ofstigmasterol, sitosterol, fucosterol, brassicasterol, campesterol,clionasterol, desmosterol, chalinosterol, poriferasterol, and anymixture of the foregoing phytosterols; (b) a phytostanol selected fromthe group consisting of α sitostanol, β sitostanol, campestanol,brassicastanol, clionastanol, stigmastanol, desmostanol, chalinostanol,poriferastanol, 22, 23 dihydrobrassicastanol, and any mixture of theforegoing phytostanols; (c) lutein, (d) Coenzyme Q₁₀, (e) isoflavones,(f) and a mixture of any of the foregoing esters.
 14. The method asdefined in claim 11, wherein said triglyceride is selected from thegroup consisting of sunflower oil, soy bean oil, olive oil, a mediumchain triglyceride selected from the group containing fatty acidsranging from C₆ to C₁₂ and a mixture of any of the foregoingtriglycerides.
 15. The method as defined in claim 11, wherein saidessential oil extractive is one selected from the group consisting oforange oil, lime oil, clove oil, oregano oil, peppermint oil, cinnamonoil and a mixture of any of the foregoing extractives.
 16. The method asdefined in claim 11, wherein said dispersion agent is selected from thegroup consisting of (a) a lecithin, (b) a hydrocolloid, (c) a surfactantand (d) a mixture of any of the foregoing dispersion agents.
 17. Themethod as defined in claim 11, wherein said lecithin is selected fromthe group consisting of a lecithin derived from soybean and a lecithinderived from egg.
 18. The method as defined in claim 17, wherein saidhydrocolloid is selected from a group consisting of xantham gum, starch,pectin, gelatin, guar gum, carrageenan, methylcellulose, hydroxypropylcellulose and a mixture of the foregoing hydrocolloids.
 19. The methodas defined in claim 17, wherein said surfactant is selected from thegroup consisting of celtylpyridinium chloride, polysorbate 80, sorbitanmonostearate, a polyglycerol ester, a block copolymer of propyleneoxide, ethylene oxide and a mixture of any of the forgoing surfactants.